PROJECT SUMMARY/ABSTRACT The prefrontal cortex (PFC) plays a crucial role in cognitive behaviors that are disrupted in many, if not all, psychiatric disorders. It is also responsible for integrating a number of subcortical excitatory inputs, including from the mediodorsal nucleus of the thalamus (MD) and the basolateral amygdala (BLA). These inputs are also implicated in many PFC-dependent behaviors and symptoms of these psychiatric disorders. For instance, connectivity between the MD and the PFC is essential for working memory, but is disrupted in patients with schizophrenia. Notably, this hypoconnectivity is also found in adolescents with a clinical high risk for schizophrenia, serving as a predictor of later illness conversion, which may indicate an important role for these circuits in the development of the disorder. Adolescence is a vulnerable time window in the progression of psychiatric disorders, and it is also a period of maturation of PFC circuitry. Therefore, during this period, the brain may be more susceptible to external signals, and transient perturbations can result in persistent changes in circuitry. In sensory cortex (e.g., visual system), there are ?sensitive periods? when transient disruption of one excitatory input (e.g., one eye) leads to rewiring of thalamocortical connections as well as sensory impairments (e.g., amblyopia) that persist even after the input has been restored. This proposal aims to discover if there is a competitive, activity-dependent sensitive period during adolescence that governs the maturation of medial PFC (mPFC) circuits in mice, similar to what has been described in other cortical regions. This question will be tested using a combination of transgenic mouse models, viral inhibitory DREADD constructs, behavioral tests, viral tracers for anatomical studies, and slice electrophysiology. Aim 1 will discover whether there is indeed a sensitive period in adolescence or adulthood during which transient inhibition of the MD will have persistent consequences on behaviors that are dependent both on MD-mPFC circuitry and BLA- mPFC circuitry. Aim 2 will use anatomical labeling and in vitro slice electrophysiology to discover whether transient MD inhibition can persistently disrupt the densities and strengths of excitatory projections to the mPFC. These studies will discover mechanisms that govern the development of inputs into the mPFC, and may also be instructive for understanding the circuit how a developmental imbalance in activity between different subcortical inputs can increase risk for developing a psychiatric disorder.